Autoimmune disorders occur when an immune response is directed to endogenous or "self" proteins that are recognized as "foreign" antigens. Immune response consists of the production of antibodies and the activation of T cells that react with these antigens and initiate a series of destructive changes. The tolerance to "self" antigens is induced in early lymphocyte development by the specific clonal deletion of cells which recognize "self" antigens and is supported by cell--cell interactions, cytokine and immunosuppressive factors, and induction of anergy. The breakdown of tolerance to "self" proteins can occur by a variety of mechanisms. T cells can be stimulated by cross-reacting microbial antigens which have features in common with self antigens, as in rheumatic fever and chronic synovial inflammatory processes. Normally sequestered proteins that become exposed to immune surveillance through tissue changes, as in Hashimoto's thyroiditis, will activate a population of cells that were not originally clonally deleted. There is a correlation between specific major histocompatibility loci (MHC) and susceptibility to certain autoimmune disorders, indicating that multiple components may contribute to disease induction.
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that results from the destruction of the insulin-secreting beta-cells of the pancreas. Patients with IDDM have insulitis, a lymphocytic infiltration of the islets of Langerhans, islet-specific Th1 lymphocytes, and antibodies directed against components of the islet cells. IDDM in animal models is T cell mediated and requires the participation of both CD8+, class I MHC restricted and CD4+, class II MHC restricted T cells. There is a demonstrated association between MHC class II DR4 polymorphic alleles and disease susceptibility, indicating that the response is antigen driven. Peptide elution studies indicate that these polymorphisms may modify suceptability to IDDM by selectively affecting the nature of the molecules presented to T cells by these class II molecules (Wicker, L. S. et al. (1995) Annu. Rev. Immunol. 13: 179-200; Reich, E. P. et al. (1994) J. Immunol. 152: 2279-2288).
Several beta-cell proteins have been identified as candidate antigens in IDDM. Antibodies to two glutamate acid decarboxylase isoforms, insulin, carboxypeptidase H, ICA 516 and 64 kD integral membrane proteins, hsp65, and several secretory granule protein have been found in the sera of diabetic and prediabetic individuals. Peripheral blood T cells from a majority of persons newly diagnosed with IDDM respond to a variety of insulin-secretory granule antigens. A mouse insulin-secretory granule antigen (imogen 38) has recently been isolated by using an assay based on the proliferative response of a human IDDM T cell clone. Although this isolated antigen is a mitochondrial protein which occurs in various tissues the imogen 38-reactive antibodies are found only in the diseased pancreatic tissue (Roep, B. O. (1996) Diabetes 45: 1147-1156; and Arden, S. A. et al (1996) J. Clin. Invest. 97: 551-561).
The discovery of an autoantigen-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of immune disorders.